By Steve Augustyn

September 25th 2023

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Steve Augustyn

Senior Consultant Mechanical Engineer

Trends in respiratory therapies: why pMDIs hang in the balance of new technology

In May 2023, RDD Europe returned to a real-world conference after years of pandemic-enforced online-only presence. The location was spectacular – Antibes on the Cote d’Azur – with the sparkling Mediterranean Sea providing welcome relief from a dismal British spring.

The industry was well represented by device technology companies, CMOs, academics and pharma companies, and the presentations and workshops provided an engaging blend of research and practical advice.

Even though much of my time over the past ten years has been focused on parenteral device development, my career in combination products started in respiratory devices, working on a variety of dry powder inhaler (DPI) and pressurised metered dose inhaler (pMDI) devices, including the GSK Ellipta inhaler. This year at RDD, as I returned to my roots in this industry, three main themes struck me: preparing for the pMDI cliff edge; moving beyond traditional respiratory diseases; and implementing particle engineering for targeted treatment.

There were also two notable omissions: users and connectivity. More on those later.

Preparing for the cliff edge of pMDI propellants

The shift in pMDIs from using HFC propellants towards gases with a lower global warming potential (GWP) has gained momentum, with California imposing a ban on the sale and distribution of R227ea from the end of 2030, and R134a from the end of 2032, including for medical use. This means the end of the line for the sale of all current pMDI products in California, with other jurisdictions likely to follow suit as the world tries to move to a more sustainable solution.

The transition needs formulators, device designers, scientists, and other disciplines to collaborate to solve the challenges presented by the different physical properties of the new gases. Different thermodynamic and fluid dynamic properties can dramatically alter the plume geometry, droplet size and particle velocity, requiring careful redesign of the fluid pathways to compensate for the differences. These challenges were outlined in evidence presented by Recipharm (1), Proveris and Koura (2), and Healthy Airways LLC (3).

At Cambridge Design Partnership, we are receiving far fewer enquiries for pMDI products than DPIs and soft-mist inhalers. Obviously, an n=1 sample does not have a high degree of certainty, but it reflects a general sentiment among clients to focus future developments away from pMDI platforms.

Moving forward beyond traditional respiratory diseases

Asthma and COPD remain the biggest drivers in device and formulation development, much the same way that diabetes treatment has driven pen injector development. Two drivers that our drug delivery team have seen pushing device design in respiratory and the inhalation market are the need for home treatment, rather than hospital centered treatment; and platforms for biological drugs. The other significant drive is for vaccines that are stable at higher temperatures, which can be delivered without leaving behind copious volumes of blood-contaminated medical waste.

One challenge that comes with these new treatment regimens, beyond formulating drugs that will be stable in powder form, is getting the drug to the correct part of the body and making sure it remains present long enough to be effective. One paper from UCL and the University of Hong Kong (4) highlighted a promising approach to developing therapeutic antibodies against future SARS outbreaks. Some of these developments also require higher dose payloads, or API-only formulations; this presents a substantial challenge to device designers to make sure that the inhalation capabilities of different patient groups can achieve the required dose efficiency.

Aptar and Recipharm also shared their own device innovations to present novel spray and softmist technologies based on a syringe primary container. Targeting rapid treatment to the brain via the olfactory route is a much-neglected treatment option, in part due to the challenges of getting consistent behavior with users. At Cambridge Design Partnership, we’ve been working with a pioneering device company looking to exploit this pathway, and my colleague, Clare Beddoes, will be presenting information on this device development at PODD in October.

Enter: particle engineering for targeted treatment

In addition to the paper from UCL (4), particle engineering to target specific areas in the respiratory and nasal pathway was a topic that several posters and presentations addressed directly. Building on standard jet milling techniques, a paper from Aston University explained how isothermal dry particle coating (iDPC) can be used to create more potent formulations without increasing the volume of powder inhaled by the user (5). A third paper from Hovione and two Portuguese institutions focused on the characterization of different particle manufacturing techniques and how they affect deposition in nasal passages (6).

Closing the gap between the early stages of in vitro and in silico models, and the later stage in vivo performance, continues to receive a lot of attention. As the cost of computing power continues to fall, going into clinical or preclinical trials with greater confidence will accelerate time to market and reduce the cost burden on pharma companies looking to novel treatments.

Don’t forget user capability and connectivity

Two areas of development that received relatively little focus at the conference were human factors engineering (HFE) and connectivity – two concerns that are the subject of a great deal of effort in the parenteral sector. Recipharm presented a poster on the HFE advantages of their novel unit dose nasal spray when compared to a reference device (which bore a striking resemblance to an Aptar Unidose Liquid Nasal Spray). Research institution Solvias presented a paper showing how training users can lead to worse outcomes due to misperception of expertise using a device (7). This counterintuitive result demonstrated that patients with limited one-to-one training with a Handihaler showed more errors in use than patients who only had access to the device and IFU.

While these insights were welcome, our in-house team knows that patients continue to struggle to use inhalers reliably and consistently, leaving even the most effective drug products showing variable results.

These challenges for patient use are also being seen in the parenteral market, which is why we are working so closely with our clients to find better ways to train patients and leverage connectivity to improve adherence to medication regimens. These connectivity solutions are often in direct conflict with cost and sustainability targets and finding a route to square this circle is a challenge with which CDP’s designers and engineers are actively engaging.

See you in Tucson?

RDD 2023 was the first RDD conference I have attended. It was great to reconnect with former colleagues and make new connections across the industry. The conference was very well run, and the standard of papers and presentations ensured there was plenty of fascinating material for industry and academia to engage with. I’ve already blocked out my diary for RDD 2024 in Tucson and I look forward to seeing you there.

References

1. 1. Albuterol Sulfate Metered Dose Inhaler Feasibility Using an Environment Friendly Propellant HFA152a and Novel Valves (Lei Mao, Sheryl Johnson, Nischal Pant, James Murray, Donald Ellis, Benjamin Zechinati, Johnathan Carr and Victoria Cruttenden)
1. 1. Comparison of Spray Characteristics of P-134a and Low GWP P-152a pMDIs With and Without Ethanol (Lynn Jordan, Sheryl Johnson, Ramesh Chand, Grant Thurston, Deborah Jones, Vanessa Webster and Sally Stanford)
1. 1. Accelerated Development of MDIs with Low GWP Propellants in a QbD Era: Practical, Regulatory and Scientific Considerations (Healthy Airways LLC and First Flight Pharma LLC)
1. 1. Inhaled Antibody Therapies: Enabling Prophylactic Protection against SARS-CoV-2 Infection with a Dual Targeting Powder Formulation (Han Song Saw and Jenny Ka-Wing Lam)
1. 1. Use of Isothermal Dry Particle Coating (iDPC) for the Development of High Dose Dry Powder Inhalers (Jasdip S. Koner, David A. Wyatt, Amandip S. Gill, Shital Lungare, Rhys Jones and Afzal R. Mohammed)
1. 1. Benchmarking of Particle Engineering Strategies for Nasal Powder Delivery: Characterization of Nasal Deposition Using the Alberta Idealized Nasal Inlet (Patricia Henriques, Cláudia Costa, António Serôdio, Ana Fortuna, and Slavomíra Doktorovová)
1. 1. Effect of Capsule-Based Dry Powder Inhaler User Training on In Vitro Performance (Oleksandra Troshyna and Yannick Baschung)

Connect with CDP

For more on how to navigate the evolving respiratory device landscape, from propellant transitions to targeted delivery, contact Cambridge Design Partnership.

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By Karla Sanchez

September 21st 2023

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Karla Sanchez

Senior Consultant Biomedical Engineer

Care tech: exploring the latest trends in dementia care

We are witnessing important advances in the treatment of the most common cause of dementia, Alzheimer’s disease, most noticeably by the emergence of disease-modifying therapeutics. And this trend is only set to continue, with new innovations and technologies promising to help slow the progression of this devastating disease.

However, patients who do not yet have access to these treatments or are in a more advanced stage of the disease will continue to require significant care support. The caregiving sector is already under significant pressure due to the increasing demand for long-term care within aging populations [1]. As the disease progresses, family members, including elderly spouses, are often the main caregiver – but they may be left poorly equipped to do this without the right support.

With the cost of dementia care running to £32,250 per person per annum [2] technology innovators are finding new ways to make resources go further and give dementia patients independence for longer – providing reassurance to the caregiver and peace of mind to family members.

The challenge lies in making these solutions accessible to caregivers and usable for patients. In this article, we take a deep dive into the technologies available to support dementia care and explore emerging trends that are transforming the landscape by using the right technology at the right time.

Alzheimer’s disease is a progressive and irreversible neurodegenerative condition that primarily affects the cognitive functions of the brain, particularly memory, thinking and behavior. It is the most common cause of dementia, a broader term for a set of symptoms that impact a person’s ability to live independently.

In the UK, it is estimated that more than 900,000 people live with dementia, and this is projected to double by 2040 [3]. Of the people diagnosed, up to a third live alone [4]. With the aging population outpacing the rate of training and recruiting caregivers, the already significant caregiver shortage is set to increase [5].

Meanwhile, family members are taking on caregiver responsibilities, often with unsustainable and distressing consequences. This is in part because every patient journey is different and the rate of their disease progression can vary widely. Some patients may require discreet support at the early stages of the disease, while others may require constant care. Knowing when and how to intervene to provide the care support needed is crucial.

The care sector is increasingly looking to technology to maximize the impact of the professional and informal caregiver workforce. There is an increasing recognition that caregivers require ongoing support to make their role more manageable, especially following the pandemic.

Assistive technologies rarely exist in isolation. In fact, it is often the combination of these technologies that yields the best results. Here are some of the technologies available to support independent living and managing disease progression.

Personal alarms and safety tracking

Alarms and tracking technologies allow people to call for help if they need it – wherever they are – as well as providing peace of mind for caregivers and family members when they are not there. They are simple to use and can help patients stay independent for longer.

Location. GPS trackers such as Mindme, Ubeequee, and Angelsense consist of battery powered or rechargeable wearables that connect to a 24/7 monitoring support center to alert family members and emergency services if a vulnerable adult is outside designated safe zones. Direct-to-consumer devices, such as Medpage, work similarly, but the information links directly to family members and may not have predefined safety zones or raise an alarm. Connectivity is based on broadband and subject to subscription charges.

Alarms and calls. Technologies such as Tunstall’s MyAmie, Oysta, and Saga’s SOS allow patients to raise an alarm for relatives, caregivers or emergency services with the use of a single button. These technologies often come in the form of a pendant worn around the house and are connected to a hub via a radio signal. The patient can also use the hub to raise an alarm. The pendant must be within reach of the hub for it to work. Other technologies, however, work similarly to the GPS tracker and can rely on broadband for wider network reach. These technologies often also incorporate fall detection and GPS.

Fall detection. Wearables such as Buddi, Telecare, and Careline are designed specifically for dementia care. These use inertia measurement units, gyroscopes, and pressure sensors to detect falls and automatically send messages to caregivers, family members, and first-aid responders. These devices are often accompanied by an alarm button for the user and GPS tracking. Many of these technologies can also be connected to a 24/7 monitoring support team.

Reminders and medication adherence. There are a variety of technologies in this category which allow caregivers to set reminders for patients to take medication, drink water, eat, or remember appointments or social events. Memory aid kits available include the MemRabel care alarm clock with a large screen, connected to a Pivotell Vibratime rechargeable wrist watch that vibrates for reminders. These can be in photo, video or audio format.

The challenge many of these technologies face is that they depend on a caregiver to ensure the patient remembers to engage with and wear the device, charge it when necessary, and crucially, press the button if in distress. In the case of some technologies, they must also be within reach of a hub.

These technologies are good for the early stages of the disease, but as cognitive decline continues, patients will rely more on caregivers to support them, thus limiting their advantages.

In other words, the longevity of these technologies can become incompatible with the patient’s journey, and this is one of the key hurdles to consider when designing and adopting technology in dementia care.

Remote monitoring

This is a fast-growing area for dementia care. Remote monitoring technologies share information on the patient’s daily living patterns with caregivers and family members. The purpose is to provide peace of mind to family members and enable caregivers to make informed care decisions in the short and long term.

Common functions include:

Movement monitoring. Generally delivered by several passive infrared (PIR) sensors installed around the house, and pressure mats in beds and sofas, connected to a hub.
House occupancy. Sensors on external doors to monitor whether an individual has left the house.
Appliance usage. Monitored by connected sensors placed between the mains inlet and the device plug.
Fall detection. Cameras or mmWave radar sensors to detect when an individual has had a fall, without the need for a wearable.

Many of these functions can be delivered by single systems, e.g. Taking Care Home Alert, with the more sophisticated fall detection systems generally targeted at professional care provider users, e.g. Hikvision and Vayyar Care.

It is also common for families to create their own solutions, especially when they feel no existing single solution works for them. This includes the use of consumer tech, such as smartphones, video doorbells, smart home speakers, and cameras around the house. Video doorbells, for example, can be valuable in preventing scams, while smart home speakers can set reminders, automate house functions, or call a relative. However, the use of cameras around the house does pose privacy concerns which need to be considered.

Although the overall objective is to monitor daily independent living, the information often requires interpretation by the caregiver. This can often be facilitated through a dashboard, although the information can be disjointed, and assessment of patterns may not be clear-cut.

Innovator Matt Ash from Supersense Technologies, however, believes we can do more to obtain valuable insights and monitor disease progression efficiently and noninvasively.

“There is a real need for technologies that support caregivers in their role and provide them with the confidence to take a break, knowing their loved one is safe. Though there are some credible assistive technologies out there, the unique needs of families living with dementia are not well served. Projects like the Longitude Prize on Dementia are investing in radical thinking to generate solutions with families living with dementia.”

Talking about some of the latest advancements being tested, Ash continues:

“Everyone’s journey with dementia is different. Right now, we are working on leveraging recent consumer developments in sensor technology, machine learning, and user experience to create personalized assistive systems that can evolve with the needs of an individual with dementia and their caregivers. It’s an incredible opportunity to provide the community with supporting technologies that serve their needs.”

If we want to empower those with dementia to live independently, maximize the impact of caregivers, and provide peace of mind to family members, we must enable the right type of intervention at the right time. Someone with early Alzheimer’s disease may feel overwhelmed or suspicious of new technology, while a person in later stages may be too vulnerable to learn how to use it.

The future of dementia care will center around collecting the right data and extracting the right insights from it to enable better care choices. By allowing technology to provide information on the progression rate of the disease for a particular patient, we can start building a profile of care by recognizing changes in patterns to a baseline. Emerging technologies such as remote monitoring platforms can support this and guide the longevity of other technological interventions to ensure that they align with the individual patient’s journey. At the heart of these technologies, privacy must be a top priority, which may include the use of AI and other methods to allow for patterns to be recognized quickly and with minimal need of human intervention.

We are entering a new era of therapeutics for Alzheimer’s disease, but there is still much to do, particularly in care. Although the use of technology can ultimately support patients, caregivers and family members, it is often incompatible with the individual’s stage of the disease, or inaccessible to caregivers. But as new technologies emerge, data and AI can unlock new insights to support a personalized care plan that scopes each patient to their individual needs – allowing caregivers and families to provide the best care at the right time.

References

E. adult social care insight. The size and structure of the adult social care sector and workforce in England. Technical report, Skills for Care, Workforce Intelligence, 2023.
Alzheimer’s Society, How much does dementia care cost? https://www.alzheimers.org.uk/blog/how-much-does-dementia-care-cost
L. B.-A. A. R. Raphael Wittenberg, Bo Hu. Projections of older people with dementia and costs of dementia care in the United Kingdom, 2019–2040. Technical report, Care Policy and Evaluation Centre, London School of Economics and Political Science, 2019.
B. W. Claudia Miranda-Castillo and M. Orrell. People with dementia living alone: what are their needs and what kind of support are they receiving? International Psychogeriatrics, 2010.
E. adult social care insight. The size and structure of the adult social care sector and workforce in England. Technical report, Skills for Care, Workforce Intelligence, 2023.

Connect with CDP

For more on how to accelerate patient-centred innovation in dementia care technology and device design, contact Cambridge Design Partnership.

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By Karla Sanchez

June 21st 2023

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Karla Sanchez

Senior Consultant Biomedical Engineer

Neurodegenerative conditions: turning a corner to better treatment?

Pace is accelerating for tackling neurodegenerative diseases. Can we unlock better treatment? Can we reach a cure?

Ageing populations face neurodegenerative conditions, such as Alzheimer’s Disease, Parkinson’s Disease, Motor Neurone Disease, Multiple Sclerosis, and others. These impact an estimated 60 million people worldwide, equivalent to the current UK population.

Whilst each condition has different mechanisms of neurodegeneration, they all have something in common: prognosis is bleak, treatment is limited, and there is no cure.

However, after decades of research, there has been a series of breakthroughs. Here, we focus on two areas of progress: how treatments have moved on and hope for the future.

The rise of RNA-based therapeutics

The effective development of RNA-based vaccines during the COVID-19 outbreak catapulted RNA-based therapeutics into the spotlight. Whilst theoretical knowledge of RNA therapy has existed for over 30 years, the bulk of associated FDA approval for treatments involving the nervous system has occurred in the last decade⁽¹⁾.

A major advantage of RNA-based therapy over conventional small molecule and protein-based approaches is its high specificity and precision, resulting in a more targeted approach to treating disease with specific gene mutations or overexpression.

However, to devise effective RNA-based therapeutics, the genetic hallmarks of the neurodegenerative disease of interest must be known.

Motor Neurone Disease (MND) is one such condition where specific mutations in the SOD1 gene have been identified and in this case, in two per cent of diagnosed cases.

A recent breakthrough in phase three clinical trials targeted this gene using the drug Tofersen. Tofersen, developed by Biogen, directly interferes with the faulty overproduction of SOD1. After six months, patients had a reduction in SOD1 levels, and after 12 months the same patients reported better mobility and lung function^(2,3). Although patients with SOD1 mutations only represent two per cent of those living with MND, these trials provide ‘proof of concept’ that similar gene therapy-based approaches may help other forms of the disease.

Another pioneering strategy, developed by Atalanta Therapeutics and Genentech, focuses on a technology called branched siRNA (small interference RNA). This is a type of molecule that helps regulate gene expression by binding to a complementary messenger RNA, which in turn can encode the gene of interest.

Branched siRNA uses novel RNA interference nucleotide technology to suppress the activity of genes that function abnormally, such as mutations. This slows the progression of the disease or stops it altogether.

It is hoped this approach can be applied across multiple neurodegenerative diseases, including Parkinson’s Disease, Huntington’s Disease and Alzheimer’s Disease.

Although testing is still in the pre-clinical stage, the branched siRNA platform aims to enable RNA interference to be deployed as a therapeutic approach throughout the brain and spinal cord. This overcomes the long-standing challenge of achieving adequate distribution within the central nervous system (CNS) to ensure the therapeutic agent reaches the nervous tissue^(4,5).

Progress in non-RNA therapeutics

Non-RNA therapeutics for neurodegenerative conditions also continue to progress. Examples include the monoclonal antibody Donanemab, developed by Eli Lilly. Phase three clinical trials showed it to slow clinical decline by 35% in patients with Alzheimer’s Disease, compared to a placebo⁽⁶⁾.

Effective delivery remains a major challenge

One of the main challenges in developing RNA therapeutics, and therapeutics for the brain in general, remains the efficiency of its delivery to the target tissue.

To treat neurodegenerative conditions, the therapeutic agent aims to reach the CNS. The presence of the blood-brain barrier (BBB), a cell-formed wall separating the bloodstream and the CNS, makes it difficult to deliver drugs. The BBB’s almost impermeable characteristics allow very few molecules to cross and make systemic drug delivery less efficacious.

There are two common approaches to overcome this: re-engineering the therapeutic agent to make it compatible with BBB permeability or bypassing the BBB altogether.

Re-engineering the therapeutic agent

This typically involves chemical modification of the drug (e.g., from water-soluble to lipid-soluble molecules) to enable passive diffusion through the BBB. Another approach is to design drug carriers that mimic the structure of endogenous molecules (e.g., monosaccharides, hormones) to activate carrier-mediated transport or nanocarriers^(7,8). Both approaches add complexity to manufacturing.

Another cross-BBB approach is Focused Ultrasound (FUS), where high-intensity sound waves temporarily disrupt the BBB to enable drug-loaded microbubbles to enter the CNS⁹.

Bypassing the blood-brain barrier

Bypassing the BBB can save time and effort in formulation by using a range of therapeutic agents not constricted by size or BBB compatibility. Of its three most common types of delivery: intraparenchymal, intranasal, and cerebrospinal fluid (CSF) delivery; the latter is often the favored approach, due to lower clinical complexity¹⁰.

Evaluating CSF delivery routes

CSF delivery most commonly include intrathecal (IT) or intraventricular (ICV) routes.

IT involves an injection either on the lumbar or a cisterna magna region to deliver the drug and let CSF pulsatile flow support the distribution of the therapeutic agent in the brain and spinal cord.

ICV is more invasive. It involves two surgical interventions, one to place a catheter connecting the cerebral ventricles to the injection port at the top of the skull and one to remove the catheter.

To date, ICV has two approved drugs (Rituxan for CNS Lymphoma, and Brineura for Neuronal Ceroid Lipofuscinoses type two). IT lumbar injection has one (Spiranza for Spinal Muscular Atrophy) and plenty more in clinical and pre-clinical stages across a spectrum of neurodegenerative and neurological diseases⁽¹¹⁾. Irrespective of the approach, the trend is clear: less invasive, lower dosage, and targeted delivery is the way to go.

In the race to show safety and efficacy with either invasive or non-invasive approaches, all solutions will have to be patient-centered.

A new dawn for the treatment of neurodegenerative diseases

The complexities of neurodegeneration have long frustrated scientists and clinicians alike, despite decades dedicated to studying its diseases, aetiologies, and treatments. However, we are making more rapid and more significant progress.

We have some way to go, but we mustn’t overlook the magnitude of these milestones. New therapeutics and delivery techniques are paving the way to more effective and efficient treatment.

By increasing our understanding of genetic hallmarks of the diseases, and using tools such as AI in drug discovery, we can unlock faster pathways to RNA-based treatments. Similarly, by finding innovative ways of demonstrating the safety and efficacy of delivery methods, such as modeling, we can edge closer to less invasive procedures and lower dosages to minimize potential side effects.

We need more research, more awareness, earlier diagnosis, and a better understanding of risk factors to enable prevention and earlier intervention.

But we are now getting closer to better treatment and one day finding a cure.

References

http://nectar.northampton.ac.uk/16015/1/Anthony_Karen_RNAB_2022_RNA_based_therapeutics_for_neurological_diseases.pdf
https://www.sheffield.ac.uk/neuroscience-institute/news/promising-mnd-drug-helps-slow-disease-progression-and-benefits-patients-physically
https://www.nejm.org/doi/full/10.1056/NEJMoa2204705
https://www.gene.com/stories/pioneering-novel-therapeutics-in-neuroscience
https://www.nature.com/articles/s41587-019-0205-0
https://clinicaltrials.gov/ct2/show/NCT04437511?term=TRAILBLAZER-ALZ&cond=Alzheimer+Disease&draw=2&rank=3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905930/
https://ijponline.biomedcentral.com/articles/10.1186/s13052-018-0563-0#:~:text=Modification%20of%20the%20drug%20to,capable%20of%20crossing%20the%20BBB.
https://clinicaltrials.gov/ct2/show/NCT03321487
https://www.frontiersin.org/articles/10.3389/fnagi.2019.00373/full
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305158/

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For more on how to advance RNA therapeutics and targeted CNS drug delivery for neurodegenerative diseases, contact Cambridge Design Partnership.

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By Alejandra Sanchez and Carla Greig

June 20th 2023

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Alejandra Sanchez

Consultant Biomedical Engineer

Carla Greig

Consultant Biomedical Scientist

Could oligonucleotide manufacturing advances redefine therapy?

Oligonucleotides have the potential to address some of the most devastating diseases that remain stubbornly resistant to treatment. These include neurodegenerative, vascular, respiratory, and oncological illnesses. As exciting as this branch of science is, the oligo industry is still in its commercial infancy. Large-scale oligonucleotide manufacturing is not straightforward, and various challenges need addressing.

To understand these, Alejandra and Carla, two Consultant biomedical engineers at Cambridge Design Partnership (CDP), were invited to take part in the Innovation in Oligonucleotide Manufacturing Symposium hosted by CPI at their new facilities in Glasgow. After an intensive day of discussion between key stakeholders from industry, academia, government, and the regulatory sector, we present the main takeaways. For this to make sense, let’s start from the beginning.

How do oligonucleotides work?

Oligonucleotides are short DNA or RNA molecules, typically around 20 nucleotides (basic building blocks of nucleic acids) in length. They can modulate gene expression, the process by which information included in a gene informs the assembly of a protein molecule. They do this by binding to pre-mRNA and mRNA, the carriers of genetic information before the mature mRNA is translated into proteins. Because mRNAs carry code for all cellular proteins, oligonucleotides could be effective for targets and diseases not treatable by current drugs¹.

What is their importance as therapeutic agents?

Oligonucleotide therapeutics prevent or modulate the expression of almost any gene as part of highly targeted treatment. They aim to target the genetic basis of the disease rather than the symptoms. Compared to conventional therapies, oligonucleotides have a higher specificity with reduced side effects. They can target specific molecules that are currently difficult to target, such as RNA. Several oligonucleotide therapeutics are already on the market, with Novartis Pharmaceutical’s Vitravene, for treating cytomegalovirus retinitis in immunocompromised patients, being the first to be approved by the FDA in 1998.

The list of diseases that oligonucleotides can target is ever-growing, with the market valued at USD 5.19 billion in 2020 and expected to rise to USD 26.09 billion by 2030².

How are oligonucleotides manufactured?

Oligonucleotides are synthesized chemically, where nucleotides are added stepwise, resulting in a growing chain. Each nucleotide is subjected to a series of chemical reactions to create a stable component allowing the chain to grow.

The two different types of oligonucleotide manufacturing are solid-phase and liquid-phase synthesis. Solid-phase oligonucleotide synthesis is carried out on a solid insoluble object, such as polystyrene beads, placed in columns that enable all reagents and solvents to pass through freely.

In liquid-phase synthesis, the oligonucleotides are grown on soluble polymeric support within a homogeneous media; the polymer-bound product is commonly recovered from the reaction mixture by precipitation, thus allowing the rapid elimination of excess reagent and soluble by-products.

Solid phase allows high throughput synthesis and purification, with liquid phase taking longer to synthesize the oligonucleotides. However, liquid-phase has the advantage of being performed on a larger scale and typically being less expensive than solid-phase synthesis. Once the desired oligonucleotide has been synthesized, the material can be passed to the next processing steps, including purification, concentration and, commonly, lyophilization.

What are the main challenges in the process?

Oligonucleotide manufacturing is a complex process with many limitations, especially in scalability. The major problems researchers face are currently due to high expenses regarding the raw materials for oligonucleotide synthesis, a lack of funding for oligonucleotide therapies, and a shortage of skilled resources in the oligonucleotide synthesis field. These problems create substantial bottlenecks in the research required for therapeutic oligonucleotides and, ultimately, the clinical use of these therapies.

Key takeaways on the manufacturing of oligonucleotides

Moving towards liquid-phase oligonucleotide synthesis. Solid-phase oligonucleotide synthesis is a great tool for rapidly making lots of oligos in the lab. However, it has drawbacks when manufacturing hundreds of kg or even multi-ton quantities per year, which might be the case for emergent nucleotide products targeting more common diseases³.
The major problems include:
- As the oligo grows, the space for the fresh nucleotides to diffuse and react gets tight, leading to incomplete couplings. This results in an altered sequence of monomers and incorrect genetic information in the final product, which must be removed by extensive and expensive processes.
- It is hard to scale up the solid beds (insoluble particles to which the oligonucleotide is bound during synthesis).
- The synthesis and purification steps generate large amounts of organic and aqueous waste.

Liquid-phase synthesis stands as a promising approach to increase the yield of the overall process while allowing the production of large amounts of oligonucleotides in, potentially, a more sustainable manner⁴.

New alternatives to current purification methods are under investigation. Promising approaches to simplifying the purification steps show good results in the investigational phase5. Examples are membrane-sieving technology and biocatalytic processes used for phase separation. In the biocatalytic process, oligonucleotides are synthesized in a single operation, with fewer impurities and by-product production, and in aqueous media. All these are promising features that target the current limitations of existing synthesis methods3.

New approaches come with new challenges: The development of novel and alternative technologies offers opportunities to address some of the limitations of solid-phase synthesis while also creating new challenges. For instance, using nanofiltration membranes to support the synthesis of oligonucleotides in liquid phase can present issues such as membrane stability and fouling. Another concern regarding the enzymatic approach is the availability of raw material with the right purity.
If we consider the bigger picture, another novel approach in the pharmaceutical industry is the adoption of digital manufacturing technologies. However, this up-and-coming tool may come with its own challenges due to lack of pharmaceutical manufacturing expertise and the high cost of initial funds.

Raw materials suppliers are already working towards reducing the gap. Strategies to reduce the prices of chemicals and deliver sustainable solutions are already underway. For instance, Honeywell US, a major supplier of the raw material required for oligonucleotide production, recycles solvents and assigns dedicated chemical drums to individual businesses to avoid cross-contamination.

Big wins for early pioneers

At CDP, we see every challenge as an opportunity, and we are pleased to know that governments and large industries have already recognized these problems. Major efforts to accelerate research in the UK have been launched, not only as funding from governmental innovation agencies but also from pharmaceutical companies. In addition, the 18 oligonucleotide therapies already approved by the US Food and Drug Administration (FDA) for clinical use are leading the way⁶.

There is a need for rapid adoption of next-generation processes that reduce risk, cut costs and save time while enabling on-demand therapies for every patient. However, regulatory-wise, standards in this industry are yet to be established. The risk around safety and efficacy remains a significant concern: How do we ensure we have the right sequence in each molecule? How do these molecules behave for a specific treatment? And what is the risk for the patient? These are just a few questions that still need to be addressed.

The event at CPI highlighted the importance of bringing experts together to shape the path and accelerate innovation. Understanding the challenges in the oligonucleotide space and planning around them will allow us to drive successful manufacturing at scale. The moment to build the future is now!

References

Kole R, Krainer AR, Altman S. Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40. doi: 10.1038/nrd3625.
Allied Market Research, Oligonucleotide Synthesis Market report, Code A08356, July 2021
Sarah Lovelock, “Biocatalytic approaches to therapeutic oligonucleotide manufacture” in “Enzyme Engineering XXVI”, Andy Bommarius, Georgia Institute of Technology, USA; Vesna Mitchell, Codexis, USA; Doug Fuerst, GSK, USA Eds, ECI Symposium Series, (2022). https://dc.engconfintl.org/enzyme_xxvi/37. Abstract: https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1034&context=enzyme_xxvi&type=additional
J. Org. Chem. 2021, 86, 1, 49–61 Publication Date: November 30, 2020 https://doi.org/10.1021/acs.joc.0c02291
Dousis A, Ravichandran K, Hobert EM, Moore MJ, Rabideau AE. Nat Biotechnol. 2023 Apr;41(4):560-568. doi: 10.1038/s41587-022-01525-6.
Martin Egli, Muthiah Manoharan, Nucleic Acids Research, Volume 51, Issue 6, 11 April 2023, Pages 2529–2573.

By Matt Morris and Shweta Shewale

April 26th 2023

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Matt Morris

Senior consultant mechanical engineer

Shweta Shewale

Mechanical Engineer

Are we there yet? An honest progress report on our environmental sustainability

“We’re all on a mission to achieve sustainability, working together to build a better business for people and planet”. While it may be true, statements like this don’t offer much insight into what we’re actually doing about our environmental impact. Instead, we’d like to provide an honest assessment of where we are now, what actions we’ve taken so far, and where we’re focusing our efforts in the future.

Sustainability communications are often full of cliché. In their excellent research report ‘Words that work’, creative communications consultancy Radley Yeldar analyzed the websites of 50 of the Forbes 100 most valuable brands and found the same words and phrases repeatedly cropping up. One of the most popular was the notion of a ‘sustainability journey’.

We can see how this happens – in fact, in the first draft of this article, we followed this same path. We want to talk about the progress we’ve made, which we’re proud of, but we know we’ve got a long way to go. We’ve got plans that we want to share – how do we communicate this process while it’s happening? There’s an obvious metaphor!

Part of the reason brands lapse into cliché, says Radley Yeldar, is fear of criticism if they’re brutally honest. So, we’ll try to take their advice, and be brave. Here goes.

An honest assessment

CDP is an Employee-Owned company. A little over a year ago, a group of employee-owners, supported by the management team, started an initiative to measure our performance against the B Impact Assessment, a widely used framework for all-round sustainability impact. Overall, we were very happy with how we measured up – many of the policies, actions and outcomes the assessment checks for were already established.

However, one of the reasons to go through this process was to identify any gaps in our performance. There was one area we decided to focus on, because frankly it was a little behind many other parts of the assessment – our work to improve our environmental sustainability.

What makes us want to improve?

Beyond a desire to have the most positive impact we can, there were three compelling reasons for us to take action:

We’re delighted that more and more of the global brands we work with are committing to ambitious environmental sustainability targets – we want to help them achieve these goals and give them the confidence that we are just as committed to having a positive environmental impact.
We work hard to reflect the needs and priorities of our employee-owners – our only shareholder and biggest asset. Surveys and engagement events have made clear that environmental sustainability is important to them.
We have recently transitioned to a ‘large’ company under UK law, which entails new reporting requirements – the perfect time, therefore, to embed new measurement and reporting systems across the company.

Making a change through our client work

There are two ways that we can have an impact on the environment – through our business operations, and through the innovation, design, and development work we do on behalf of our clients.

Whilst we feel it’s important to minimize the environmental impact of our own operations, helping our clients to ‘improve lives through innovation’ (our purpose) allows us to contribute to environmental and social benefits at a scale well beyond that which we can achieve alone. As an example, a quick calculation showed that the annual production of a particular dry powder inhaler – a typical project we might deliver for a client – was responsible for more than 50 times our annual carbon footprint. Or, put another way, if we helped a client to reduce the carbon impact of that product by just 2%, we would save the equivalent of CDP’s annual carbon footprint.

Recognizing this, we’ve invested in growing our capability in sustainability and cleantech, helping our clients reduce their environmental impact and develop new technologies, including:

Developing packaging design and sustainability guidelines for one of the world’s largest consumer packaged goods companies
Helping multiple blue chip clients transition from fossil-fuel-derived plastic packaging to alternatives such as paper. Highlights include a patented, first-of-its-kind, single-mold paper bottle for Pulpex
Performing a life cycle assessment to benchmark the environmental impacts of a connected autoinjector, and using this to drive design changes that minimize these impacts
Designing and developing a pop-up solar car park and electric vehicle charging hub for 3ti Energy Hubs, which won Best New Product at The Electric Vehicle Innovation & Excellence Awards (EVIEs)
Winning a hackathon run by Cambridge Institute for Sustainability Leadership (CISL) and British Antarctic Survey (BAS) to help BAS achieve net zero at their Rothera research station in Antarctica

Changes in our own operations

In the last year, we’ve also made significant progress on how our business operations impact the environment; much of this was enabled through moving to a new purpose-built facility, which involved over three years of rigorous planning and attention to detail:

Net zero HQ

Our new UK headquarters at Bourn Quarter is built to be net zero over its lifetime. It doesn’t rely on fossil fuels for heating and is designed to high standards of energy efficiency. On-site power generation includes 1,500m2 of rooftop solar panels across our Innovation Centre and Pilot Production Centre buildings – that’s an area larger than five tennis courts!

Supply network with shared values

Recognizing that much of our impact occurs through our suppliers, we’re starting to factor environmental impact into our supplier selection. In the last year, we’ve brought in Wilson Vale as our catering partner – their central operations are certified carbon neutral, and at Bourn Quarter they serve seasonal food and take steps to minimize food waste. They calculate how many people are typically on-site on certain days and incorporate any leftovers into the following day’s meals – for example, as an option in the salad bar.

Measuring what matters

Our science and engineering teams know that accurate data is crucial to optimizing any process. So, we’ve set up systems to monitor our energy use, carbon emissions, and waste – the areas of greatest impact from our operations. Electricity consumption data from our first few months in Bourn Quarter will allow us to optimize our heating and lighting usage. We’re also collecting data on our recycling, food and general waste streams, to generate insights that will support future improvements.

Awareness and engagement

We’ve worked hard to bring our entire organization with us, so that everyone feels ready and empowered to help identify and solve problems. This type of unified effort reflects the culture of our company, rather than a passion project for a small group of champions working in isolation.

We’re achieving this through regular all-company ‘town hall’, updates, interactive ‘lunch and learns’, and immersive Climate Fresk sessions – three- to four-hour workshops which explore the fundamental science behind climate change.

Are we there yet?

Whilst we’re proud of what we’ve achieved so far, it’s just the start of an ongoing process to manage and improve our environmental impact, and we’ve got a lot more work to do! As Peter Drucker famously put it, “you can’t improve what you don’t measure” – quantifying our carbon, waste and water impact is the foundation for both transparent reporting and further progress. We’re looking forward to using the measurement and analysis systems we’ve established to benchmark our performance and assess the effect of improvements we make. We plan to publish our first impact report later this year – and we’ll be aiming for openness, honesty, and a minimum of sustainability cliché!

If you have similar ambitions and would like to discuss this in more detail – particularly if you’re close to Cambridge (UK) or Raleigh, North Carolina (USA) – please get in contact.

By Mark Allen

January 25th 2023

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Mark Allen

Consultant Mechanical Engineer

Key trends in respiratory drug delivery

It was great to be back in person for the Drug Delivery to the Lungs conference in Edinburgh recently. Here, we share insights on three major themes from the event and a trend we think will reshape the future of respiratory drug delivery in the next 10-20 years.

Sustainable pMDIs

The shift in pMDIs from using HFC propellants towards less polluting gases has gained momentum with California imposing a ban on the sale and distribution of R227ea from the end of 2030 and R134a from the end of 2032, including medical use. This provides an end-of-the-line for the sale of all current pMDI products in California.

The transition needs formulators, device designers, scientists, and other disciplines to collaborate to solve the challenges presented by the different physical properties of the new gases. The assessment of all types of inhalers from a sustainability perspective has advanced, too, with life cycle analysis (LCA) and carbon credits schemes being discussed – our sustainability team provides reviews and recommendations for a range of medical devices to help our clients improve their devices and provide evidence to back up their green credentials.

Usability for adherence

Time and again, studies show that it’s challenging to measure asthma and COPD patients’ adherence to their medication. Medication adherence appears much lower than for other diseases – estimates range from 22-78% adherence, compared to 70% for diabetes.

Low adherence needs to be addressed by making devices easier to use and tailoring them to the patient’s needs. Reducing user steps is key to make using the device easier, but patient feedback and tailoring to specific needs are necessary, too – something connected inhalers could help solve through digital reminders appropriate to the patient’s needs. Independently verifying that increased adherence is due to connected or smart inhalers is difficult to prove – something the industry is investigating.

Modelling of drug delivery

Several talks at this year’s event covered modelling, with in-silico methods advancing in capability and popularity over the last 10 years. Topics covered included constructing a full airway model to assess drug deposition under different breathing profiles and using maths with physiological signals to detect disease and drug-induced changes. Posters demonstrated an even wider range of possible models, including our own.

Our modelling and simulation teams produce models for clients that highlight potential robustness issues with mechanical components and digital sensing techniques at early stages to determine suitable technologies for medical devices.

Learning from the past, looking to the future

Federico Lavorini, Professor and Consultant in Respiratory Medicine at the Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy, gave an excellent summary of drug delivery over the last 100 years, including innovations where design has reduced user error.

Further talks considered what pharma could learn from other markets, especially as we move from ‘sick care’ to ‘health care’ – where technology identifies and treats conditions before they become symptomatic. Our Drug Delivery and Insight & Strategy teams work closely together to understand upcoming trends and draw on insights into consumer expectations from the consumer and digital markets for our clients.

Biologic treatments are coming to respiratory drug delivery and are likely to use Soft Mist Inhalers (SMIs) and Dry Powder Inhalers (DPIs) for delivery, with current trends looking to lean heavily on DPIs. This is likely to lead to the development of new, higher-performance DPIs to provide the best efficiency delivering these high-cost treatments to the patient. We have dramatically increased the performance of DPI engines for our clients through our science-based approach to increase fine particle fraction for their devices.

How we can help

Our team are experienced in all stages of the development of drug delivery devices for a wide range of scenarios and applications in the medical industry, with a dedicated team working in these areas. Here at CDP, we have these specialists all under one roof to partner with you to bring your device to market and can also draw on the learnings of our colleagues in consumer markets to guide on relevant future consumer expectations.

By Richard Owen

November 18th 2022

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Richard Owen

Senior Consultant Bio-scientist

Five ways to take cultured meat mainstream

Better for the environment and better for animals, cultured meat is an ascendant industry and could grow even faster with these five improvements.

COP27 climate negotiations look set to conclude with steady – if not stellar – progress on reaching a consensus as to how the world can avoid catastrophic climate change. However, one area almost absent in the outcomes so far is how we can reduce the environmental impact of animal agriculture, which is estimated to make up 20% of global greenhouse gas emissions – that’s more than the entire global transport sector.

That doesn’t mean nothing is happening. In recent years, we’ve seen massive investment in one potential solution to this problem: Cultured meat, grown in a lab from a few animal cells, has the potential to counter some of the biggest issues facing humanity, including global warming, land degradation, and water usage.

On November 16, the sector marked a significant milestone as the US Food and Drug Administration (FDA) raised no questions to UPSIDE Foods pre-market consultation for its cultured chicken products for human consumption. It needs final approval and isn’t on sale yet, but this is a significant hurdle crossed.

How can the cultured meat sector build on this moment and realize the enormous potential to contribute to a sustainable future? We’ve identified five steps producers need to take:

1) Think differently to scale up efficiently

We know we can make cultured meat, but the costs and scale mean it isn’t yet an everyday item. Pharma-style processes and equipment just aren’t designed for food-based products and so won’t get the sector where it needs to be.

We need a mix of new thinking, processes, and products. Rather than focus on pharma, technology should be brought in from other sectors, such as the brewing, textiles, and food ingredients industries, as their process throughput and manufacturing costs are closer to what’s needed for this market.

Ingredients and structural components must be fully defined and standardized before cell bio-fermentation can become a high throughput, low intervention process, like brewing or baking.

2) Don’t obsess about patents

While patents are critical to many industries and bio-based start-ups, they aren’t so important in the cultured meat sector. Most companies have specific cell lines, cell sources, ingredients, and fermentation protocols.

Due to the way cells develop according to their genotype and environment, they’re highly likely to develop in a unique way. Patenting engineered cell lines, cell collection procedures, formulation recipes, differentiation techniques or fermentation protocols is unnecessary, as they would be very difficult to replicate.

It’s much better to keep the know-how in-house, in a similar way to the ‘secret recipes’ of malt whisky manufacturers – they all start with water, yeast and malted barley, but make very different products.

3) Think beyond the butchers

Many cultured meats closely replicate products you’d find on a butcher’s block. While the industry is young, this gently introduces consumers to a new type of product.

However, there’s huge potential to make new products that aren’t replicas of butcher-shop cuts. How about mixing and matching cell textures, fat content, and fiber lengths to create a cross between pate and streaky bacon?

Amazing new products could be created, potentially formulated to be cooked to a certain style, e.g. slow-cooked or medium rare. This could excite consumers and show that this new technique could create a whole new and exciting range of meat products.

4) Get the branding right

Cultured meat companies have a lot of heavy lifting to do to educate the consumer. Meat in its raw state is often considered a generic product; only after cooking does it normally appear as a brand.

Linkage to other existing brands is one option, such as endorsement by well-known chefs or restaurants. Other options include trying to emulate exotic breeds such as Wagyu beef, ostrich, or kudu (antelope). First-movers will have an advantage; later entrants may have to specialize to grab and retain a niche.

5) Embrace the difference between pharma and food products

The pharma industry has advanced the science used by cultured meat producers.

However, the goal of cultured meat producers is to produce a tasty, safe piece of food, rather than a viable drug therapeutic that must engraft in a patient and perform a complex variety of immunological functions.

This means costs and testing procedures should be very different. Much of the cost of pharma production of cell and gene therapies lies in sample collection and testing during manufacture and quality control. There’s a huge list of different attributes that need to be tested, from intracellular mycoplasma to cell viability, potency, and cellular identity.

Conversely, once the manufacturing process for cultured meat has been appropriately established and validated, automated in-process monitoring can remove the need for almost all final batch-based tests.

In addition, more automated diagnostic-style testing regimes can be used instead of the labor-intensive R&D-style analytical methods.

Meat the pioneers

GOOD Meat cultivated meat brand is part of the California-based sustainable food company Eat Just. Its products have already launched in Singapore. In Autumn 2021, it raised $97 million in funding, adding to another $170 million raised in Spring.

California-based UPSIDE Foods has the claim to fame that it cultivated the world’s first beef meatball. In Spring 2022, it raised $400 million in Series C funding to drive product innovation and infrastructure to make cultured meat at scale.

References

Valdmanis R, Cocks T. Meat on the menu, not the agenda, at cop27 climate conference [Internet]. Reuters. Thomson Reuters; 2022 [cited 2022Nov17]. Available from: https://www.reuters.com/business/cop/meat-menu-not-agenda-cop27-climate-conference-2022-11-15/

Pre-market consultation for human food made using animal cell culture [Internet]. U.S. Food and Drug Administration. FDA; 2022 [cited 2022Nov17]. Available from: https://www.fda.gov/food/cfsan-constituent-updates/fda-completes-first-pre-market-consultation-human-food-made-using-animal-cell-culture-technology

Gelski J. Good meat raises $97 million in latest funding round [Internet]. Meat Poultry. Sosland Publishing; 2021 [cited 2022Nov16]. Available from: https://www.meatpoultry.com/articles/25539-good-meat-raises-97-million-in-latest-funding-round

Hood LL. Huge facility to produce 15,000 tons of lab grown meat per year in the US [Internet]. Futurism. Camden Media Inc; 2022 [cited 2022Nov16]. Available from: https://futurism.com/the-byte/biggest-cultivated-grown-meat-lab

Series C funding brings the upside of meat one (giant) step closer [Internet]. UPSIDE Foods. UPSIDE Foods; 2022 [cited 2022Nov16]. Available from: https://upsidefoods.com/upside-series-c-fundraising-round/

Clinical Manufacturing

We manufacture Class II and III medical devices – mechanical and electronic, durable and consumable – for our global clients. So, we understand the barriers they face getting their product from design to manufacture for clinical trials.

We’ve invested in the advanced clinical manufacturing facilities, domain expertise, and compliance to overcome our clients’ challenges, from fulfilling the volumes to managing the complexity of the set-ups they need. We’re capable of producing up to 100,000 devices under ISO 13485:2016 certified QMS by Intertek Medical Notified Body, harnessing leading-edge facilities such as ISO Class 7 cleanrooms and our purpose-built 26,000 sq ft UK manufacturing center.

Class II and III medical devices
Capacity for up to 100,000 devices
26,000 sq ft UK manufacturing center
QMS ISO 13485:2016 by Intertek Medical Notified Body

Our expertise extends across aseptic filling and sterilization, which we deliver through collaboration with our proven partners, as well as performing device assembly, labeling, and logistics in-house.

We regularly conduct design verification testing, including developing bespoke test methods, which we subsequently validate, managing the entire validation process for our clients. We create the documentation for design history and technical files, and support with the regulatory submission.

Our clients trust us to advance their Class II and III medical devices, from design to clinical manufacture. These devices create a fast track to user studies and clinical trials, then onwards to the clinic and regulatory submission. Our clinical manufacturing capability, shaped by years of practical experience and harnessed for the world’s leading healthcare companies, is proof of the purpose that unites us: to improve lives through innovation.

Assembly
Aseptic filling & sterilization
Labeling
Logistics
Design verification testing
Packaging
Technical and design history file assembly

Clinical-Manufacturing-I28A0355-ADH-700w

By Richard Owen

November 10th 2022

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on LinkedIn:

Richard Owen

Senior Consultant Bio-scientist

Digital PCR – a technology set to transform clinical testing?

Pregnancy screening, cancer treatment, organ transplant – digital PCR testing has the power to enhance clinical decision-making. But what is needed to take it mainstream?

Polymerase Chain Reaction (PCR) testing has reached unlikely levels of fame due to the COVID-19 pandemic. However, its latest evolution, digital PCR, could be a real game-changer for commercial diagnostics.

The power of digital PCR

When people talk about PCR testing, they often refer to quantitative PCR. This technology is fantastic at delivering binary answers, for example, whether a disease is present or not. It can also determine to some extent how much of a disease is present in a sample (though the process is inaccurate). Quantitative PCR’s quantification can be improved by calibrators, but this is complex, expensive, and time-consuming for a lab to perform.

Digital PCR advances this technology to deliver precise quantification and improves detection of low-frequency DNA targets.

The potential to transform clinical decision-making

The key benefit of digital PCR can be summed up in two words: better data. It has the power to transform clinical decision-making, for example, in the following areas:

Pregnancy screening

Highly accurate testing for chromosomal trisomies, such as Down’s syndrome, by detecting traces of foetal DNA in maternal blood. Next-generation sequencing (NGS) is an existing alternative but has extremely complex protocols, including DNA purification, DNA library preparation, sequencing, data alignment, and analysis.

Cancer treatment

Pinpointing disease progression by detecting tumor DNA in liquid biopsies.

Organ transplants

Detecting DNA sequences leaking from a donor organ (a sign that the host immune system is rejecting it).

Virus detection

Increasing accuracy in treatment of HIV, hepatitis C, herpes, cytomegalovirus, and other infections.

Disease diagnostics

Quantification of bacterial species in stools due to digital PCR’s lower sensitivity to inhibitors.

Digital PCR could also deliver accurate quantification of levels of other infectious diseases such as respiratory viruses and sexually transmitted infections. This precision isn’t currently available but could be useful for clinicians to differentiate between different stages of infection.

How does digital PCR differ from quantitative PCR?

Digital PCR is a development of ‘standard’ PCR, using the same concept of exponential amplification of template DNA with DNA primers and a polymerase enzyme. It has two crucial differences: compartmentalization and end-point data collection.

Compartmentalization

Instead of performing a reaction on a whole sample, digital PCR splits the sample across a large number of separate compartments. ‘Compartment’ could mean a microfluidics chip, or a droplet suspended in an emulsion.

Each reaction is capable of detecting a single molecule of DNA. A larger number of amplification cycles are generally run, typically 60 versus 40 for standard PCR. Just one DNA molecule in a compartment is enough to initiate a PCR amplification reaction.

End-point data collection

Unlike quantitative PCR which reads after every amplification cycle, digital PCR just needs to read once when all the amplification cycles are complete. This is an important saving, as otherwise, all the thousands of individual compartments would need to be read every cycle, which would be a significant challenge.

Digital PCR overview

What’s stopping the mass adoption of digital PCR?

Though digital PCR has been around for 20 years and is mentioned in thousands of patents, only a handful of commercial products use the technology. The primary challenge innovators need to crack for it to go mainstream is optimal compartmentalization.

Cracking compartmentalization

Compartmentalization affects key performance parameters, such as the assay’s dynamic range, linearity, accuracy and ease of use; its cost; whether it’s run as a batch or on-demand; and how many samples can be run at once. The number of compartments in the assay must be high, relative to the concentration of input DNA molecules in the sample. But if the assay uses too few compartments, the accuracy of quantification will be too low, and the assay must be repeated using a diluted sample.

Why does compartment design matter?

Digital PCR’s randomly apportioned target molecules across a large number of compartments mean there will be some compartments with no targets, some with one, and a few with two or more. As it’s not known how many target molecules are in each positive compartment, the Poisson distribution is used to determine the most likely proportions of compartments with one, two, three, or more DNA targets. Using the Poisson distribution allows accurate quantification, but relies on two important factors:

The input template being randomly spread throughout all the reaction chambers
All compartments being the same size

These are critical parameters, and there are two main ways to achieve them. The first is passing the sample over a microfluidic flow cell containing microwells commonly filled using capillary action. The second is encapsulating the nucleic acid in a huge number of water droplets in an emulsion of oil, with each droplet containing a separate reaction.

Microfluidic droplet generator developed at CDP

The ideal compartmentalization system would retain the ease of use of current quantitative PCR systems and have a similar lab-bench footprint and costs. However, current approaches (typically involving microfluidics or droplets), require multiple complex disposables and sophisticated optics. If a new approach was developed with lower costs, clinicians and test centers may well convert to digital PCR for all their applications. The company that manages to crack this challenge has the potential to dominate the PCR market and provide huge advances to clinical decision making.

To talk to us about our current innovation in the field of digital PCR, get in touch.

September 14th 2022

Designing more sustainable electronics

From phones to laptops, home devices to watches, electronic devices – particularly smart devices – have become part of people’s lives, enabling better communication and access to information and making their day-to-day easier.

But the increasing adoption of technology comes at an environmental cost. Electronic devices often have a significant carbon footprint because of the energy-intensive processes needed to produce printed circuit boards (PCBs) and integrated circuits.

Electronics production relies on mining and extracting dozens of different materials, including critical raw materials (economically important materials at high risk of supply shortage, such as lithium or titanium). Extracting these materials has a range of sustainability impacts, including the leakage of toxic chemicals such as cyanide into the environment, high levels of water use, and human rights abuses in the case of ‘conflict minerals’ such as gold and tantalum.

Waste electronic products, or e-waste, is the fastest-growing waste stream in the world, with over 53 million tonnes of e-waste produced in 2019. Most e-waste is disposed of incorrectly, ending up at waste dumps in developing countries. Hazardous chemicals, such as lead or mercury, that may be present in electronic components can leak into the environment, harming local ecosystems and damaging the health of people who live and work in the dumps.

Product sustainability has focused on the circular economy, particularly recycling. But there are fundamental limits to the impact recycling can have on electronics. Only 17% of e-waste is collected for recycling and, even if it’s collected, recovering materials from e-waste is particularly challenging.

Electronics contain trace amounts of rare metals, which are complex and expensive to separate. Only the most abundant materials, such as copper and gold, can be economically retrieved during e-waste recycling, and even if all e-waste was recycled in this way, the material recovered still wouldn’t be enough to meet the growing demands of the industry.

One way to tackle the environmental challenges presented by electronics is to remove the need for them in the first place, for example by detecting a temperature change using a color-changing chemical rather than a sensor. But, in some instances, electronics are necessary, so how can designers reduce the impact of the products they create?

Our sustainability team assessed a range of technologies and design techniques to determine their potential for reducing the environmental impact of electronic products and how difficult they are to implement. This article outlines a few approaches we’ve used in recent projects at CDP.

web_graph_designing-more-sustainable-electronics

Reducing complexity through connectivity

One of the best ways to reduce an electronic device’s environmental impact is by minimizing the electronics’ complexity, thereby reducing the number of integrated circuits needed as well as the surrounding passive components (resistors, capacitors and so on), connecting tracks, and PCB area.

An easy, effective way to do this is by pairing a product with a user’s existing device to provide the smart capability. Methods range from a simple QR code or NFC chip to a Bluetooth connection for transferring more complex data.

As well as reducing the electronics in the product, this allows for a degree of futureproofing, as software updates can be used to keep the product up to date. This idea isn’t new but is starting to be used more in applications from smart packaging to medical devices.

Important to note: Behind many of these software solutions are large data centers that need powering and should be considered in the product’s environmental impact.

Informed decision-making: Life Cycle Assessment (LCA)

Designers can optimize component choices and circuit designs during detailed design to reduce the overall impact of a product.

We recently used LCA to estimate the additional carbon footprint of adding an electronic module to a medical device. This step allowed our team to identify where to focus on reducing the impact of the design, such as replacing integrated circuits with a solution based on lower-impact passive components and optimizing the layout to minimize the total area of PCB required.

We identified several solutions that together had the potential to reduce the total carbon footprint of the product by up to 25% without compromising functionality. In many cases, this optimization also generates cost savings.

Optimizing electronics through additive manufacturing

Over the past two decades, additive manufacturing (such as 3D printing) has seen a surge in use in mechanical prototyping and manufacture, and its applications in the electronics sector are now starting to grow. In the context of PCBs, additive manufacturing refers to selectively adding conductive material to the areas required, as opposed to a more traditional approach which starts with a layer of copper and selectively etches away the areas where it isn’t needed.

These technologies can improve a product’s carbon footprint through reduced material usage and less energy-intensive manufacturing processes. A report published by the ECOtronics project found, “Changing from subtractive manufacturing (etching) to additive manufacturing (printing) has the potential to reduce environmental impacts by more than 50% across all impact categories.”

One additive manufacturing method is laser direct structuring (LDS), which allows you to construct circuits on the surface of device components. With this approach, you can remove the PCB entirely, dramatically cutting down on the material required.

These technologies present opportunities to fit electronics into new form factors, print onto a wide array of rigid or flexible substrates (the non-conductive part of the circuit board the metal circuit is added to) and increase the customizability of the design, all while reducing the product’s environmental impact.

As we’ve highlighted before, sustainability initiatives should always consider context, which is vital for electronics. In the absence of cost-effective recycling processes, designers must prioritize approaches that reduce the materials and energy required to produce electronics. As electronics continue to play a leading role in our lives, future designs should reduce our reliance on critical raw materials and consider how circular approaches to design can extend product lifetimes and prevent harm to people and the environment.

References

Conflict minerals used in IT products drive wars and human rights abuses [Internet]. TCO Certified. [cited 19 August 2022]. Available from: https://tcocertified.com/conflict-minerals/
Global E-waste Monitor 2020 [Internet]. ITU. [cited 19 August 2022]. Available from: https://www.itu.int/en/ITU-D/Environment/Pages/Spotlight/Global-Ewaste-Monitor-2020.aspx
ECOtronics [Internet]. ECOtronics. [cited 19 August 2022]. Available from: https://www.ecotronics.fi/

Connect with CDP

For more on how to reduce the environmental impact of your electronics through smarter design choices, contact Cambridge Design Partnership.

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